Exon skipping – waiting, worrying, and limited information

AVI issued a press release earlier this week. If you read the press release you will read that the DMD program AVI 4658 is on “clinical hold”. This means that the FDA’s position is that they do not have sufficient data to agree it is safe to move forward. In the past months, AVI has changed its leadership, recruiting individuals who have experience in drug development in rare disease. Several of these individuals came from Genzyme. AVI is currently in discussions with FDA in an effort to provide sufficient information to lift the clinical hold.

In parallel AVI is moving forward internally, developing protocols and identifying sites for clinical trials. NO recruiting can take place for exon 51 until the ‘clinical hold’ is removed. It is illegal and unethical. I understand that many of you contacted Jerry Mendell and other sites about the trial but at the moment there are no trials and there can be no recruiting.

Here’s what we know about the current status of exon skipping:

Prosensa has completed their dose escalation trial. We know that their chemistry is safe thus far and that the subcutaneous injection of the chemistry resulted skipping exon 51 and production of a shortened (truncated) form of Dystrophin. We do not know if this protein is efficient – if it results in improved function.

The AVI chemistry (PMO) has been injected IV in the UK trial. Again, we know that thus far it is safe and that it successfully skipped exon 51 and resulted in a shortened form of the protein. We do not know if this shortened protein is efficient at this time.

There is a basic assumption that skipping a single exon, restoring the frame with expression of the shortened protein will result in stabilization of function, slowing degeneration, and functional improvement. This is the reason for clinical trials (human studies). We have mouse data, human muscle data (in culture), and dog data (PMO – 2 dogs). I realize we have our hearts on this strategy and with good reason, but we cannot put the cart before the horse at this moment.

We can expect Prosensa will move forward in multi-site trials, hopefully this year. They will need sufficient numbers of patients (exon 51) for proof of concept. They also plan to skip exon 44 with trials in the US.

Hopefully AVI’s discussions with FDA will result in lifting the clinical hold and clinical trials with exon 51. There is discussion about additional exons to include 50, 53, and 46, as well as discussions about second generation compounds, adding a peptide( PPMO) to the chemistry to improve efficiency.

Seems we have been hearing about exon skipping for years. Duchenne Parent Project (the Netherlands) and PPMD initially invested in this strategy in 1998. Statistically, it takes about 10-12 years for drug development, so we are at the forefront of trials and (cross fingers and pray) the trials will provide proof of concept. BUT we have to have trials and those trials are going to take some time - and it will be nerve racking, frustrating, and difficult. There are no shortcuts and no one gets in line before another. Once FDA gives the green light, the trials will be public knowledge and boys that are potential candidates will be screened. ALL potential candidates will be screened – blood work, genetic testing (re-testing), biopsy, functional testing. They will need sufficient boys in each trial in order to ‘power’ the trials and hopefully demonstrate proof of concept.

Once there is ‘proof of concept” on at least one or more exons, we are all hopeful FDA and EMEA will agree to streamline the process to accelerate chemistries for other mutations.

To me, the really good news is that both companies have recruited leadership from Genzyme, individuals experienced in the drug development process in rare disorders. My interpretation is that industry leaders see that antisense oligonucleoties are very promising and very likely to provide benefit to Duchenne.

The most difficult thing is the wait...and we have all been waiting since that word Duchenne entered our homes.

Things to think about:
1. Don’t make guesses. There are loads of rumors, try your very best not to get caught up in them.
2. Register on DuchenneConnect (www.duchenneconnect.org). The moment a trial is open for recruitment, you will be notified.
3. Understand that boys who qualify will be screened. For proof of concept, large numbers of boys will be needed for the trials. Those who fit the mutation criteria and fit the protocol will be screened and included.

The community feels fractured, the ‘haves’ and the ‘have –nots’ with so many feeling their sons might be on the outside of treatment and cure. The field is ripe with possibilities. Please (I’m begging here) understand that we are going to do everything possible to accelerate every opportunity. Discussions based in anger, rumor, or guesses divide us…just when we need to stick together and watch the sun rise for our boys.

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Comment by cheryl cliff on May 14, 2009 at 8:17pm
Hi Mindy,

Frankly I am glad you posted information about upcoming trials. I consider this website my eyes and ears for what can, will or should happen next. Even if the news turns out bad I still need to know what is going on. It's easy to read good intentions from your posts, very clear you mean well and I would have done the exact same as you if I had been given the information you had. DMD is a very tough world so sorting through some confusion is no big deal. And you didn't cause confusion or create any harm in any way so please don't worry.

I'll let you know when Paul is ready to organize your garage - he is still sharpening things :) - gotta keep that pitchfork handy!
Comment by Ofelia Marin on May 14, 2009 at 3:22pm
Mindy, I do not think you mislead anyone. For me, reading those posts, it was very clear that they are sizing the population and that, when more info will be available, they will communicate it. Also, the site never said that the trial was ready to start and they also had several discussions with AVI before they started estimating the possible candidate population, they did not act by themselves. Mendell also said that they are in discussions with FDA (by them I mean AVI and the site) but the clinical hold was not lifted. So, no confusion there. Also, I think it is normal for us to have questions and try to find the correct answers. My son is not even at the age when he could participate in these trials and I asked plenty of questions. I am not concerned if anyone is offended. I want to learn all I can and be informed about all possible trials as well as standards of care to be able to make the right decisions for my son.

Last year, I was very surprised that DuchenneConnect did not inform anyone about the start of Prosensa's systemic trial, nor was it posted before we read about it in Prosensa's web page. So in my opinion the communication from DuchenneConnect is not as hoped. My son was registered since diagnosis and I update his profile every year but I was not notified about any of these 2 trails, Prosensa's and AVI's.

Comment by Pat Furlong on May 14, 2009 at 3:20pm
Hello Mindy. I will speak with Vanessa about the info. on DuchenneConnect. You are most welcome to contact her as well. DuchenneConnect is ONE vehicle. There will be any number of connections -through the clinic, Clinical Trials.gov, DuchenneConnect, PPMD website, google alerts to name a few. I would be hooked up to everything possible and I think it is absolutely wonderful to contact anyone you feel could provide information.
Until the FDA gives the go-ahead, no one will be able to discuss protocols or recruitment. It is my guess that biopsies will be involved - pre and post in these upcoming clinical trials. They will need to confirm protein expression and quantify the amout of dystrophin present. There is no way around it.
I also understand you are terrified and trying to weigh prosensa's chemistry vs AVI. The reality is that this is exactly the reason for clinical trials. There are no guarantees unfortunately. Both chemistries (single muscle and short term systemic trials) are apparently safe. I think your question is actually -what is the best chemistry for your son. And there is no answer at the moment. Perhaps both? or one might work better for some children. This is what the clinical trials are designed to find out.
Typically in the Phase I and ii a trials, sites try to recruit the patients (small numbers) from nearby to the clinic. This for safety, so that if something goes wrong, the family is close by. I understand you would move to the UK if needed, would stay for weeks or months if that would help, but the reality is that the early trials involve small numbers. If successful, the trials will expand to include multiple sites because the trials will require significant numbers in order to prove effect.
Think about the 124 trials. The phase I trials involved healthy volunteers.
Exon skipping phase I started with injection to a single muscle -small numbers
Phase IIa exon skipping again involved small numbers -dose escalation to determine therapeutic dose
Next trials - Phase II B will involve 100+/- boys.
In the PTC trial -126 boys were to be recruited, 26 sites. Because it takes time to recruit, screen and conduct the trial. Typically sites had an average of around 6-8 boys in the trial, some less, some more. The expanded exon 51 trials will be widely advertised, that is sure.
I understand you feel like you are gambling with your sons' lives, but early trials are "due diligence",, trying to decrease risk. So that when your son is screened for a trial, they have some basic knowledge about safety of the compounds They have knowledge about therapeutic dose. And the expanded trials will answer the question of benefit. It is not easy. The informed consent will scare the beegeebees out of you. It is frightening for sure. But so is Duchenne and I don't say that lightly. The families in the ptc124 trial are warriors, taking a leap for all of us. At the end of the day, exon skipping is an opportunity.
There is no doubt of your good intentions. We are all doing the best we can and it is not easy. \
Comment by Mindy on May 14, 2009 at 2:46pm
Pat - I'm not trying to do anything "illegal", "unethical" or divisive. I'm just trying to get the most current information I possibly can. If we're supposed to use DuchenneConnect as the way to get the most current information about clinical trials, it has very out of date information posted about exon skipping.

Here's what it says currently about the UK trials:
Sponsor Imperial College London
Reference NCT00159250
Status Phase 1/Phase 2
Recruiting Start Date
End Date October 2007
December 2008

I tried to contact the site in the UK as soon as the systemic trials information was posted, and I was told that the study was already full - entirely filled with patients from that clinic. Can we be confident in the fact that DuchenneConnect is the vehicle that researchers will use in recruiting patients, and that it will be their first step in doing so?

And Ofelia is correct - in the conversations I had with Columbus, they were simply assessing interest, not recruiting patients. I initially contacted them to ask if I should get a muscle biopsy in preparation for participation in any upcoming trials. If I misled any parents out there, I apologize.

We're all trying to act in good faith, with good intentions, in the interests of our sons. And we're all trying to do the best that we can.

As parents of boys who can hopefully benefit from exon skipping, there are some difficult decisions ahead. When do we participate in trials? Do we try to get into a Prosensa trial, or do we wait for AVI? At times, it feels like we're going to Vegas, except we're gambling our sons instead of money. Of course we're going to try and find out all we can about details before making those kinds of terrifying decisions.
Comment by Ian Anthony Griffiths on May 14, 2009 at 1:32pm
Thanks Pat, I realise i'm not forgotten, Time is of the essence for myself and others over 21. I had an idea of artifical bionic muscles replacing our muscles, only the key breathing and heart, maybe arm muscles. With all the will in the world, if my muscles have gone past a critical point there will be no saving them. If we think out of the box, and work out a mechanical solution in the body to buy us time. I have heard of the first steps on the bbc http://news.bbc.co.uk/1/hi/health/4817848.stm Its probably a poor idea, but I like the concept. Id need my fibrosis cut in my hand to open my hand, but my hospital wont think of doing that, plus they do not want me using anaesthetics at all, or painkillers, so i'd doubt operations would be carried out. I dont even have a neuromuscular consultant to ask about my dmd anyway.

Comment by Pat Furlong on May 14, 2009 at 12:36pm
Hello Ian, You are right that a great deal of the approach is directed to young boys. I can imagine that must make you feel horrible and left out. None of us have written you off, not at all. I wish research moved faster and I do know that if any or all of these strategies provide benefit, they would expand trials to everyone. We continue to discuss the possibility of 'small miracles', interventions that would improve hand strength.
One project we have discussed in the international meeting is robotics, developing an invisible anti-gravity device that would make arm movement possible. We are anxious to fund this through UPPMD, so please understand you (and all adults with DMD) are definitely not forgotten, not for one moment.
Comment by Ian Anthony Griffiths on May 14, 2009 at 10:57am
Im 24 with dmd, im on a vent 15 hours daily, FVC of 6%, really bad hand, arm, leg contractures, spinal curvatures and dysphagia, have cardiomyopathy, with increasing doses of beta blockers and ACE inhibitors. What can Exon skipping do for me, I doubt i have much muscle left now? I dont hear it mentioned with 20+ year olds? Is there nothing for us "older" guys, or are we a written off generation? Its fantastic hope for the children, i'm really glad there is hope. I gotta think about me aswell. Good article though.
Comment by cheryl cliff on May 14, 2009 at 9:53am
Hi Pat,

I for one occasionally need your reminders and reassurance that things are moving, and in a positive direction. Paul and I both trust who you are and what you are doing for Alexander and all the guys.

Please let us know what we can do to change the landscape regarding heart transplants.
Comment by Jacobs Mommom on May 14, 2009 at 9:00am
You go on and on Pat! What you wrote is something that I FINALLY understand. No medical mumbo jumbo but straight from the heart and it is greatly appreciated:)

Comment by Pat Furlong on May 14, 2009 at 7:42am
You are right, there is a great deal of work to be done in order to get an approved therapy and there will be second generation compounds that are more efficient. I understand completely that you need something now. I understand that very well. Several weeks ago I received a dvd from a family I met more than 12 years ago. At the time of diagnosis they received the 'no help and no hope' approach from their physician. We all rejected this. The family came to ppmd conference, changed doctors, were aggressive about care. He started on steroids (weekend dose), changed to daily some years later. The family was consistent about PT, night splints, concerned about diet. Had endocrine evaluation and followed recommendations. Had cardiac evaluation and followup and taking ace inhibitors. Last year, he took a ride on his friend's ATV. Crashed, fractured left femur. Physicians said he would never walk again. It was an opinion, but not accepted. This young man is walking, now 16 and in the PTC trial. The dvd shows him walking, tossing a baseball and throwing a ball into a basket. So, this is one young man I realize. But this demonstrates the need for optimal care, aggressive care, family commitment to care. And to add to this story, the young man that received a heart transplant now 2 years ago, is driving his sister to school. These are examples of optimal care, at the right time and with the right interventions. Exon skipping is moving forward. Prosensa and AVI have compounds that hopefully will provide benefit and my guess is that whatever benefit will be on a spectrum with some boys responding really well and others achieving steady state (slower or no degeneration). No one ever pitched exon skipping as a cure. It is a step in the right direction. I understand completely you would like this disease removed from your home. You would like a day when Duchenne was not part of your thoughts or the stone you feel in your heart. Duchenne is here to stay and with luck, it will be treatable. Your sons will grow up, become adults and have a lifetime to achieve their dreams.
There are other opportunities on the horizon. We are working hard to move a therapy specifically for the heart, working with the international community to secure sufficient funds to move this into trial. (they have regulatory approval). Our drug discovery with PTC is going really well. In fact, Sharon Hesterlee (mda) said that this was the best drug discovery program on the planet. I realize this program is not in your vision and feels pretty quiet, but this is the story of drug discovery. The initial 'hits' are exciting, but the sorting through of the hits, optimizing the compopunds and testing (tox and animal testing) are boring and take time, so there is silence. And in my experience - that is, when my boys were here and i felt that stone in my heart everyday as I watched them and worried about them - the silence felt like there was nothing moving.
Care is a critical factor here and makes a great deal of difference. There should be a number of trials in the next 1-3 years.
Char, there is work going on in Prosensa and in other academic labs on the duplications. I know I must sound like a brokern record here, but first we need proof of concept on the first exons.
It is true that the research community is trying to figure out if aon will be efficient in the heart. In parallel, others are working on other ways to improve cardiac function. And keep in mind, we need to change the philosophy about Duchenne in terms of heart transplantation, not that we want all of our sons transplanted, but if they need to be transplanted, it has to be a possibility.
Like you, I hate waiting. It drives me nuts to read press releases where individuals say 'cure is near' or 'soon 13 year olds will be out of their wheelchairs'. I hate empty promises. Rather, I think we all stick together, evaluate every possibility, look under every rock and each day make sure we are doing our best for our sons, making investments in solid research, leveraging money any and every way possible and insuring that we fill gaps in care (endocrine, GI, cardiac). The dvd I mentioned is amazing in so many ways...Chris could not lift a fork at 16 and Patrick was gone. Your sons will have a far different life, but the solution is not simple and cannot be based on a single intervention. We are in a new day.... our work is to make sure there are many tomorrows.
Sorry for going on and on and on....

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